Enteral Feeding Intolerance (EFI) caused by gastric dysmotility is a serious condition in patients with critical illness admitted to Intensive Care Units (ICU), limiting the ability to administer nutrition. Food is provided to many ICU patients via nasogastric tube or similar device (“enteral feeding”). Malnutrition in the ICU, including protein malnutrition, is associated with poorer long term outcomes including increased mortality (see Malnutrition and Outcomes, Kenneth B. Christopher, M. D., International Symposium on Intensive Care and Emergency Medicine, Brussels, Belgium, Mar. 18-21, 2014). Clinical evidence of improved outcomes associated with the administration of nutrition was established in the ACCEPT study, a randomized controlled prospective trial of 462 evaluable patients that showed that improved ICU nutrition (enabled by protocolized treatment algorithms) resulted in shortened hospital stay (p=0.003) and reduced mortality (trend, p=0.058) (see Multicentre, Cluster-Randomized Clinical Trial Of Algorithms For Critical-Care Enteral And Parenteral Therapy (ACCEPT), Martin et al., CMAJ, Jan. 20, 2004; 170 (2)). Similarly, in a prospective observational cohort study of 113 ICU patients in a tertiary referral hospital, a higher provision of protein and amino acids was associated with lower mortality (Allingstrup et al. 2012 Clinical Nutrition 31 (2012) 462e468).
Gastric dysmotility is problematic in other settings where patients are generally in better health, and a variety of promotility agents have been studied. One of these, ulimorelin (see FIG. 1), has been extensively studied in humans but not yet approved for any human use. Functional activity, as measured by gastric motility and pharmacodynamic (PD) responses, was observed with ulimorelin administered as a 30 min intravenous (IV) infusion once daily in Phase 2 studies in diabetic gastroparesis patients (see Ejskjaer et al., Aliment Pharmacol Ther 29, 1179-1187) and shortened time to first bowel movement (BM) in a Phase 2 study of patients with post-operative ileus following once daily dosing (qD) for up to 7 days (see Dis Colon Rectum 2010; 53: 126-134)). In these Phase 2 studies it was observed that ulimorelin both accelerated gastric emptying of solid and liquid food (10 patients with diabetic gastroparesis) and accelerated recovery of gastrointestinal (GI) function in subjects who underwent partial large bowel resection (168 patients with post-operative ileus). An additional Phase 2 study of diabetic gastroparesis patients showed improvements in GCSI Loss of Appetite and Vomiting scores (see Ejskjaer et al., Neurogastroenterol Motil (2010) 22, 1069-e281). Unfortunately, these initial results failed to generalize as they did not reproduce in two larger prospective randomized, double-blinded, controlled pivotal Phase 3 trials of a postoperative ileus patient population when administered once daily for up to 7 days. In these larger trials, ulimorelin failed to achieve the target clinical endpoint of GI motility in patients who have undergone partial bowel resection.
Critically ill patients with EFI in the ICU are generally more ill than those studied in the ulimorelin Phase 3 trials described above. Given their serious medical condition and a general recognition of the importance of providing enteral feeding to them, these patients are often prescribed a medication in an attempt to restore gastric motility and emptying, even though current medications are unsatisfactory. Current medication choices are limited, as there are no drugs approved by the Food and Drug Administration (FDA) or EMEA, for this clinical indication. Drugs in common usage include metoclopramide and erythromycin, and to a much lesser degree, alvimopan (Entereg®) and methylnaltrexone (Relistor®). While physicians may seek to treat using up to 5-7 day courses and possibly with additional repeated courses with these medications, clinical studies demonstrate that not only is the maximal efficacy of both metoclopramide and erythromycin limited in resolving excessive gastric residual volume (GRV), but also the duration of any such efficacy is short lived, typically shorter than seven days and sometimes as little as one to two days (see Nguyen et al., Crit Care Med 2007 Vol. 35, No. 2). Among other safety concerns, metoclopramide has a “Black Box” warning from the US FDA for CNS toxicity, and use of erythromycin, an antibiotic, for a non-infectious purpose may potentially lead to bacterial resistance to antibiotics. Both of these safety issues are undesirable in the EFI intent-to-treat population.
Accordingly, there remains an unmet and urgent need for new therapies for the treatment of EFI, including in those patients who are critically ill and/or in a specialized care facility such as an ICU. The present invention meets this need and provides methods and pharmaceutical formulations and unit dose forms for the safe and efficacious treatment of EFI in the ICU and other settings.